The Many Faces of Bipolar Disorder

Dr. Heiber is a clinical pharmacist, and Dr. Purvis is a psychiatry pharmacy resident, at Western Missouri Mental Health Center in Kansas City, Missouri.

Bipolar disorder (BPD), formerly termed manic-depression, is characterized by recurrent fluctuations in mood, energy, and behavior, which impair global functioning.1,2 Genetics and environment influence this complex disorder that affects approximately 3.8% of the population.3 Clinical presentation varies widely; therefore, a complete history of symptoms is essential to diagnosis.

Four illness episodes occur in BPD: mania, depression, hypomania, and mixed (simultaneous manic and depressive symptomatology).1 The core feature of BPD is mania (bipolar I disorder) or hypomania (bipolar II disorder), which must occur only once for diagnosis. Mania is defined as persistently elevated, expansive, or irritable mood, lasting at least 1 week or requiring hospitalization. Onset is typically abrupt and symptoms escalate, lasting weeks to months. Symptoms include grandiosity, less need for sleep, pressured speech, flight of ideas, distractibility, risky behavior, and increased goal-directed activity. Hypomania is less severe, lasting for at least 4 days, without significant functional impairment.

The majority of bipolar patients experience significant enduring depression throughout life.1 In fact, they will spend more time in either a depressed or euthymic state than in mania, hypomania, or mixed mood states. Up to 40% of patients experience mixed episodes, posing a treatment challenge, often requiring augmentation strategies.1 A paucity of research exists for bipolar depression, and those with a history of mixed episodes or rapid cycling (≥4 episodes/year) are often excluded from clinical trials, which limits evidence for treatment.

Treatment Options
Several published guidelines aid clinicians in treatment selection.4-6 Lithium, valproate, and carbamazepine are treatment options approved by the FDA for acute mania/mixed episodes associated with bipolar I disorder (see the online table at www.BipolarDisorders. com for details). Carbamazepine is not considered a first-line agent due to its hematologic safety concerns.

Lamotrigine (Lamictal) is solely indicated for BPD maintenance treatment. To minimize the risk of Stevens- Johnson rash, one must titrate lamotrigine slowly (target dose 200 mg/ day), making it a poor candidate for acute treatment. Lamotrigine is thought to have a role in BPD depression; however, evidence remains limited.7

Continued therapy with a mood stabilizer remains the cornerstone for achievement and maintenance of remission. With monotherapy response rates as low as 30%, a single mood stabilizer is insufficient for many patients.8

Second-Generation Antipsychotics
The advent of second-generation antipsychotics (SGAs; eg, risperidone [Risperdal]) allowed for improved tolerability over first-generation antipsychotics (FGAs; eg, haloperidol [Haldol]). At typical dosages, SGAs cause fewer extrapyramidal side effects and less hyperprolactinemia than haloperidol and other FGAs. As few studies directly compare any SGA with traditional mood stabilizers, it cannot be said that any treatment is superior in treating BPD.

Risperidone has proven efficacy in acute mania or mixed episodes in bipolar I disorder and can be given as monotherapy or in combination with lithium or valproate. The dosage range is 2 to 6 mg/day. Side effects include somnolence, anxiety, dizziness, and dose-dependent extrapyramidal symptoms. Though occurrence is rare, hyperprolactinemia is greatest with this SGA. Weight gain and metabolic issues may also occur.

Olanzapine (Zyprexa) is indicated for the treatment of either acute or mixed mania episodes associated with bipolar I disorder and maintenance therapy. It can be prescribed as monotherapy or in combination with lithium or valproate. Frequent adverse reactions include weight gain, increases in cholesterol and other metabolic changes, as well as somnolence. The typical starting dose in BPD is 15 mg daily given at bedtime, with titration up to 20 mg as clinically indicated. Olanzapine combined with fluoxetine treats depressive episodes associated with BPD, notably with no reported increased risk of mania.9

Similarly, quetiapine (Seroquel) is indicated in acute manic episodes as either monotherapy or in combination with lithium or valproate. It is also approved for treating depressive episodes associated with BPD. Sedation, dry mouth, headache, and weight gain are frequent side effects associated with quetiapine. For depressive episodes, the target dose is 300 mg, whereas mania dosing may reach 800 mg daily.

Ziprasidone (Geodon) is another option for patients with either acute mania or mixed episodes associated with BPD. Initial dosing for mania is 80 mg/day in divided doses, and can be rapidly titrated to 160 mg/day. Absorption is increased twofold when taken with at least 500 calories.10 Somnolence, headache, and dizziness are the most commonly reported adverse events. Though ziprasidone has received negative attention for prolongation of QTc, this rarely reaches clinical significance. Routine monitoring with electrocardiogram has not been proven worthwhile; however, it is recommended in patients with cardiovascular risk factors or those taking concurrent medications known to prolong QTc.

Aripiprazole (Abilify) has indications for stabilization of acute manic or mixed episodes and maintenance therapy in BPD. It also has approval for use as a secondary agent when lithium or valproate monotherapy fails. The most commonly reported side effects for aripiprazole include headache, gastrointestinal complaints, somnolence, akathisia, agitation, and insomnia. BPD starting dose is 15 mg and can be titrated up to 30 mg daily.

Paliperidone (Invega) has not yet been evaluated for BPD treatment. The risk for agranulocytosis with clozapine deterred much study for BPD, though it is occasionally used in refractory cases.

Bipolar Depression
Beyond using quetiapine or olanzapine/ fluoxetine treatment, some data support the use of an antidepressant if the person is receiving a mood stabilizer or antipsychotic. The risk for switching to a manic episode has been reported to be as high as 40%.11 Potential correlates of this risk include signs of a mixed depression such as motor activation, pressured speech, or racing thoughts prior to treatment with the antidepressant. 12

Maintenance Treatment
As a lifelong fluctuating illness, people with BPD often require continued medication treatment. Upon achieving remission, dosage(s) may be lowered if desired; however, the 5-year relapse rate is 73% even with continued medication therapy.13

Pharmacist’s Role
Pharmacists play an essential role in optimizing treatment for a patient with BPD. Obtaining accurate medication histories is a priority with this population, helping to guide treatment selection or identify an underlying cause (eg, antidepressant use). Other valuable roles of the pharmacist include recommending appropriate dosing strategies, implementing pertinent monitoring parameters, evaluating signs and symptoms of toxicity, and increasing awareness of potential drug interactions.

Educating the patient is of utmost importance in those with BPD. Helping patients become aware of early symptoms of mania as well as depression can help them seek assistance before becoming severely ill. Providing the patient with the knowledge to prevent or treat potential side effects improves adherence to medication therapy. %u25A0